Development of a bioconversion based production platform enabled analysis of the metabolic flux and interference around two critical steps in generating the iridoid scaffold: oxidation of 8-hydroxygeraniol to the dialdehyde 8-oxogeranial followed by reductive cyclization to form nepetalactol.
A Ni-catalyzed reductive cyclization of 1,6-dienes affords 3,4-disubstituted cyclopentane and pyrrolidine derivatives with high trans diastereoselectivity.
Reductive cyclization of bromoenynamides to pyrrolidines and piperidines (n =1, 2): [Pd(PPh3)4] (2.5 mol %) and Cs2CO3 (1.5 equiv) was added to a degassed (Ar bubbling, 15 min) solution of bromoenynamide (1.0 equiv) in EtOH (0.045 m).
Reductive cyclization of bromoenynamides to piperidines (n =2) and azepanes (n =3) Method A: [Pd PPh3)4] (10 mol %) and K2CO3 (1.5 equiv) were added to a degassed (Ar bubbling, 15 min) solution of bromoenynamide (1.0 equiv) in toluene/EtOH (10 1, 0.045 m).
As outlined retrosynthetically in Scheme anie0053-7048-f 1, we envisaged late-stage unveiling the D- and E-rings through oxidation of the C13-pendant vinyl group of ABC-tricycle 2. A critical transformation would thus be the reductive cyclization of keto-butenolide 3 to establish the central B-ring and the adjacent C5 and C6 quaternary stereocenters in a single operation.
The desired stereochemical outcome of the SmI2-mediated reductive cyclization reaction of 15 is consistent with a chelated boat-type transition structure such as 19, in which the C11 substituent is equatorially disposed.
Recently, Zhang et al. proposed an NADPH-dependent reductive cyclization catalyzed by the alcohol dehydrogenase IkaC for the formation of a five-membered ring within the macrolactam ikarugomycin.
As an aside to these collected cyclization efforts, we had noted that reactions of certain substrates (e.g. 3 l) to give seven-membered ring products led to the formation of varying amounts of a byproduct featuring components of neither the boronate or stannane coupling partner, nor the characteristic alkene protons of the reductive cyclization product (5).
The benzimidazoles were effectively synthesized by a rapid 'onepot' nitro reductive cyclization reaction using sodium hydrosulfite as a reagent.
Further observations on the Diels Alder reactivity of exocyclic amidodienes formed through a reductive cyclization reveals subtle electronic effects in HDA reactions, as well as affording novel azabicyclic frameworks.
